8pnn | pdb_00008pnn
80S yeast ribosome in complex with Bromolissoclimide
Structural highlights
FunctionPublication Abstract from PubMedHalogenated natural products from marine sources often demonstrate potent activity against microorganisms and cancer cell lines. During the last three decades, the lissoclimide class of chlorinated labdane diterpenoids has been characterized with respect to structure and cytotoxic activity. Recently, our laboratories have developed different strategies to produce a broad range of naturally occurring lissoclimides and designed synthetic analogues. This work led to the discovery of a novel halogen-pi dispersion interaction between the C2 chloride of chlorolissoclimide and guanine residues in the tRNA exit (E) site of the ribosome. In this study, we aimed to synthesize lissoclimide analogues bearing different substituents in place of the chloride to investigate the importance of the halogen identity for binding, translation inhibition, and cytotoxicity. With previous access to the protio and chloro compounds (haterumaimide Q and chlorolissoclimide), we synthesized two more halogenated variants, fluorolissoclimide and bromolissoclimide, as well as a methylated analogue, methyllissoclimide, to complete a panel of chemical probes for functional and structural studies. Using an integrative approach, we explored the effects of these analogues on the eukaryotic translational machinery in vivo and in vitro. X-ray cocrystal structures with the eukaryotic ribosome were solved for each probe molecule, and the effects on ribosomal thermal stability and FRET-derived ribosome binding constants were determined. Together, these data provide a detailed understanding of the different modes of binding of lissoclimides and insight into their relative activities, which vary according to the substitutions that interact with the eukaryote-specific ribosomal protein eL42. Ultimately, we learned that the presence of a lissoclimide C2-halogen atom horizontal line offering a potentially stabilizing halogen-pi interaction horizontal line appears to facilitate or to synergize with a hydrogen-bonding interaction between the C7-hydroxyl group and the backbone of the ribosomal protein eL42, leading to stronger translation inhibition. We therefore conclude that the C2-halogen and C7-hydroxyl groups are critical contributors to potency, and this idea is borne out in the observations of reduced biological activities in the absence of either group. Synthesis of Differentially Halogenated Lissoclimide Analogues To Probe Ribosome E-Site Binding.,Terrosu S, Nurullina L, Supantanapong N, Pak BS, Nguyen S, Holm M, Wu C, Lin M, Horne D, Sachs MS, Blanchard SC, Yusupov M, Vanderwal CD ACS Chem Biol. 2025 Apr 18;20(4):858-869. doi: 10.1021/acschembio.4c00825. Epub , 2025 Mar 22. PMID:40119759[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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